Project Summary Schizophrenia (SZ) is characterized by high heritability (~80%) and elevated sibling recurrence ( s ~ 10), yet the identification of susceptibility genes has proven extremely challenging. This application entitled Next Generation Sequencing for Disease Mapping in a Founder Population aims to identify rare variants associated with illness by utilizing a unique cohort of Ashkenazi Jewish (AJ) patients with schizophrenia/schizoaffective disorder (n~1000) and well-matched Ashkenazi controls (n~2000). These samples already have GWAS data (Illumina Omni1-Quad platform) generated as part of a previously-funded project (RC2 MH089964). In this proposal, we intend to utilize next-generation sequencing to obtain high-quality, high-depth (>50x) whole-genome data from 300 cases and 500 controls selected from this cohort for maximum genomic informativeness, based on a novel genomewide haplotype sharing approach applied to the GWAS data. Due to the limited number of founders in the Ashkenazi population, we will then be able to impute >80% of all genomic variation back into the full set of samples. By contrast, the same number of samples derived from outbred European or European-American populations would permit imputation of only 20-25% of the total population variability. This imputation, combined with additional planned genotyping in the full cohort, will greatly enhance power to detect significantly associated rare variants using both single-marker and collapsing statistical approaches. Replication and extension will then be performed in publicly available SZ cohorts (e.g., GAIN) containing both AJ and non-AJ cases and controls. All DNA has already been collected and is immediately ready for sequencing. Based on our preliminary GWAS data, as well as literature from other common, complex disorders such as breast cancer and Parkinson's disease, the AJ population is likely to be enriched for a subset rare susceptibility alleles. Such alleles may therefore have higher allele frequencies and odds ratios than those detectable in other populations, providing enhanced power to detect disease-relevant loci. Notably, this enrichment can occur even in the absence of detectably increased incidence of these disorders in the AJ population. In addition to providing informative data on the role of rare variants in the genetic architecture of this devastating and disabling disorder, sequencing of the control cohort will provide an invaluable resource for future studies of many complex disorders. Moreover, computational methods development relevant to the ascertainment and interpretation of next-generation sequencing data will also be made available for sharing with the broader genetics/genomics community.